MAGEF1 is a ubiquitously expressed MAGE family protein 1 that functions as a cofactor enhancing E3 ubiquitin ligase activity. MAGEF1 forms a complex with NSMCE1 (NSE1) that promotes proteasomal degradation of MMS19, a critical component of the cytosolic iron-sulfur cluster assembly (CIA) machinery 2. By reducing MMS19 levels, MAGEF1 indirectly impairs DNA repair enzyme function, as MMS19-dependent proteins like ERCC2/XPD and FANCJ require iron-sulfur clusters as cofactors. This degradation pathway negatively regulates homologous recombination-mediated double-strand break repair, thereby suppressing genome integrity 2. MAGEF1 also interacts with PIAS1, a SUMO E3 ligase, promoting its ubiquitin-dependent degradation and inhibiting PIAS1-dependent sumoylation 3. Clinically, MAGEF1 is significantly dysregulated in hepatocellular carcinoma and associated with clinical stage and prognosis 4. MAGEF1 is notably amplified in multiple human cancer types, and amplification correlates with increased mutational burden 2, suggesting it functions as a cancer-promoting factor through CIA pathway disruption and genome destabilization.